6-25849462-T-C

Position:

• chr6-25849462-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098486.2(SLC17A3):​c.1274A>G​(p.Tyr425Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,447,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC17A3 NM_001098486.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

SLC17A3 (HGNC:10931): (solute carrier family 17 member 3) The protein encoded by this gene is a voltage-driven transporter that excretes intracellular urate and organic anions from the blood into renal tubule cells. Two transcript variants encoding different isoforms have been found for this gene. The longer isoform is a plasma membrane protein with transporter activity while the shorter isoform localizes to the endoplasmic reticulum. [provided by RefSeq, Aug 2012]

LOC124901285 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC17A3	NM_001098486.2	c.1274A>G	p.Tyr425Cys	missense_variant, splice_region_variant	11/13	ENST00000397060.8
LOC124901285	XR_007059518.1	n.380-10184T>C		intron_variant, non_coding_transcript_variant
SLC17A3	NM_006632.4	c.1040A>G	p.Tyr347Cys	missense_variant, splice_region_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC17A3	ENST00000397060.8	c.1274A>G	p.Tyr425Cys	missense_variant, splice_region_variant	11/13	2	NM_001098486.2	P1
SLC17A3	ENST00000361703.10	c.1040A>G	p.Tyr347Cys	missense_variant, splice_region_variant	10/12	1
SLC17A3	ENST00000360657.7	c.1040A>G	p.Tyr347Cys	missense_variant, splice_region_variant	10/12	2
SLC17A3	ENST00000481949.6	c.77A>G	p.Tyr26Cys	missense_variant, splice_region_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1447228 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.1040A>G (p.Y347C) alteration is located in exon 10 (coding exon 9) of the SLC17A3 gene. This alteration results from a A to G substitution at nucleotide position 1040, causing the tyrosine (Y) at amino acid position 347 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.051
FATHMM_MKL	Benign	0.072	N
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.45
MutPred		0.75		.;Loss of disorder (P = 0.1781);Loss of disorder (P = 0.1781);
MVP		0.61
MPC		0.26
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.50
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1765233462; hg19: chr6-25849690;